From: "Hu, Chuanpu" 
Subject: [NMusers] Capturing AUC between observation time intervals
Date: Wed, 3 Apr 2002 14:41:04 -0500


Dear NMusers,

A less trivial problem according to Bill Bachman as of some weeks ago. I
would like to capture the AUC (either central or peripheral compartment) at
time intervals between observations. One use of this could be to predict a
weekly-observed PD endpoint using the weekly AUC. Could anyone let me know
how something like this could be done?

Thanks,
Chuanpu

----------------------------------------------------------------
Chuanpu Hu, Ph.D.
Modeling and Simulation, U.S.
CPDM
GlaxoSmithKline
Tel: 919-483-8205  
Fax: 919-483-6380
----------------------------------------------------------------

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From: Leonid Gibiansky 
Subject: Re: [NMusers] Capturing AUC between observation time intervals
Date: Wed, 03 Apr 2002 16:42:40 -0500
 
I think you have a choice:
1. Create a data set with a lot of intermediate time points, and then come
up with the cumulative AUC=concentration*time
2. Compute AUC analytically based on the dose history and PK parameters
(the quickest way if the dose history is not too complicated)
3. Use differential equations with one of the variable being AUC (via
equation dAUC/dt=C)
4. Try to imitate (3) via additional compartment with fixed rate constants:
dA4/dt=kC4*A1-k4C*A4, k4C is about 0, kC4 is also very small but
significantly higher than k4C. Then (A4/kC4)/VC is an approximation of AUC,
if I am not mistaken (C is the central compartment).

Leonid


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From: "Sam Liao" 
Subject: RE: [NMusers] Capturing AUC between observation time intervals
Date: Wed, 3 Apr 2002 16:52:37 -0500

Hi Chuanpu:

For your question, please see the following archived nmusers msg.
http://www.cognigencorp.com/nonmem/nm/98feb192002.html
  
Best regards,
 


Sam Liao, Ph.D.
PharMax Research
270 Kerry Lane,
Blue Bell, PA 19422
phone: 215-6541151
efax: 1-720-2946783


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From: "Hu, Chuanpu" 
Subject:  RE: [NMusers] Capturing AUC between observation time intervals
Date: Wed, 3 Apr 2002 17:02:15 -0500

Leonid/Sam,

I guess my original message was not clear. Say that I have time points T1=0,
T2, T3, ... I would like to do keep AUC(T1, T2), AUC(T2,T3), etc., during
NONME fit. That is, I want to simutaneously fit PK (which drives the AUCs)
and the PD parameters to fit the PD endpoint.
Via eauation dAUC/dt=C I can compute the cumulative AUC, but somehow a
variable needs to be created to memorize the cumulative AUC at the previous
time. I do not see how the suggested approaches could be used. Am I missing
something?

Chuanpu


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From: "Hu, Chuanpu" 
Subject: RE: [NMusers] Capturing AUC between observation time intervals
Date: Wed, 3 Apr 2002 17:29:54 -0500

Leonid has a nice rephrase of the question: 

"how to store some value computed at one time point to access and update it
at another time point". 

Exactly what I would like to do. Thanks for any ideas.
Chuanpu


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From: "Sam Liao" 
Subject: RE: [NMusers] Capturing AUC between observation time intervals
Date: Wed, 3 Apr 2002 19:05:41 -0500

Chuanpu:

My mehtod will work if you fit PK and PD data sequentially.

I think I understand what you are trying to do now.  But you may need a
supper computer to run this model even if you find the way to calculate the
AUC in your PK/PD model fitting.  The AUC has to be recalculated for every
iteration for the whole treatment period.  It may take a long time to run
this model fitting.

For example, some time ago, I tried to calculate AUC based on the PK fit
parameters and daily dosing information for a 6-months PK/PD study in over
500 patients, then used the AUC to model the PD end points.  I added 10 data
points in each day to run NONMEM in simulation mode for just one patient in
order to estimate how much time will it take for over 500 patients.  I found
that for the 60-days time course, it took 7 hours and for the 30-days, it
took 10 min.  NONMEM slowed down dramatically when the no. of dosing and
observation increased.  I used a PC with 1.5 GHz Pentium 4 with 780 KB RAM
to run the job.  I found this method is not feasible to use because it will
probably take over 6 months to run the NONMEM simulation.  The other method
I used (see http://www.cognigencorp.com/nonmem/nm/98feb192002.html) only take few
minutes to run NONMEM.

Best regards,



Sam Liao, Ph.D.
PharMax Research
270 Kerry Lane,
Blue Bell, PA 19422
phone: 215-6541151
efax: 1-720-2946783


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From: Mats Karlsson 
Subject: Re: [NMusers] Capturing AUC between observation time intervals
Date: Thu, 04 Apr 2002 06:21:22 +0200

Hi Chuanpu,

I think it would work if you used the code where

DADT(x)=C

gets the cumulative AUC and then "empty" compartment X and the suitable times by
turning the CMT off and back on again (using CMT=-x and CMT=x with EVID=2 data
items). This doesn't store the old value, but would work for the problem you
described.

Best regards,
Mats

--
Mats Karlsson, PhD
Professor of Pharmacometrics
Div. of Pharmacokinetics and Drug Therapy
Dept. of Pharmaceutical Biosciences
Faculty of Pharmacy
Uppsala University
Box 591
SE-751 24 Uppsala
Sweden
phone +46 18 471 4105
fax   +46 18 471 4003
mats.karlsson@farmbio.uu.se



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From: "Hu, Chuanpu" 
Subject: RE: [NMusers] Capturing AUC between observation time intervals
Date: Thu, 4 Apr 2002 12:46:53 -0500

Mats, 

Your suggestion makes a lot of sense. Thanks a lot!

Chuanpu